Squamous cell lung carcinoma (SCC) is a form of non-small cell lung cancer that commonly arises in the primary airway. The development of SCC is closely linked to changes in squamous cells that line the airways, primarily caused by exposure to tobacco smoke. To gain insights into SCC, bioinformatics techniques have been employed to detect biomarkers and analyze gene expression patterns, utilizing data from the Cancer Genome Atlas (TCGA) database, which was preprocessed for analysis. By employing DESeq2, a differential gene expression analysis method, identified genes showed significant variations in expression between smoking and non-smoking groups among the 11,530 genes examined. Notably, five genes, namely CT45A1, GCGR, TPTE, ABCC2, and PI16, were found to play a significant role in tumor development and were susceptible to under- or over-expression due to smoking. The majority of these genes were found to be underexpressed rather than overexpressed. These identified genes hold potential as biomarkers for tumor development and exhibit a strong correlation between smoking history and the development of SCC. However, a limitation encountered during this analysis was the unavailability of data from normal non-tumor patients, which could have facilitated a more comprehensive analysis of differential gene expression. Furthermore, this research gives a deeper implementation regarding the molecular mechanisms and genomics underlying SCC development, identifies differentially expressed genes associated with SCC and smoking history, and highlights potential biomarkers that warrant further investigation.